Addressing Adverse Events in Gene Therapy


The recent FDA Advisory Committee meeting follows a turbulent year for gene therapy studies.

While gene therapies represent a revolutionary step forward in the potential treatment of many previously incurable diseases, the advent of these new therapies comes with a host of challenges. Namely, serious adverse events (AEs) associated with these therapies are garnering more attention and the mitigation of these AEs represent an unmet need in this emerging field.

To address these concerns, the FDA hosted the a meeting of the Cellular, Tissue, and Gene Therapies Advisory Committee on September 2 and 3, 2021. The meeting focused on AEs arising from adeno-associated virus (AAV) vector-delivered gene therapies, including onasemnogene abeparvovec (Zolgensma; Novartis), approved for the treatment of spinal muscular atrophy in 2019, and voretigene neparvovec (Luxturna; Spark Therapeutics), approved for the treatment of retinitis pigmentosa and Leber congenital amaurosis in 2017.

"Our enthusiasm for this field must be balanced by caution," said Wilson Bryan, director, Office of Tissues and Advanced Therapies, FDA, during the meeting’s opening presentation. "The greatest risks in drug development fall on the patients who receive an investigational product."

Among the serious AEs observed with AAV gene therapies, the committee discussed hepatoxicity, thrombotic microangiopathy, and neurotoxicity that have presented in gene therapy studies in both animals and humans. The committee also discussed the appropriate use of animal models in studying these AEs, such as mice, dogs, and non-human primates and the translatability of AEs seen in animals to humans.

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“The purpose of the meeting was for the agency to get feedback on 5 topics related to AAV gene therapy. The initial discussion [was] around tumorigenesis/oncogenesis in the context of systemic AAV gene therapy. It was mostly focused on an assay done in neonatal mice, where there's a specific site for integration of AAV vectors when given in newborn animals. None of these events have been observed in human subjects,” advisory committee member Barry Byrne, MD, PhD, director, Powell Gene Therapy Center, and associate chair, pediatrics, University of Florida, told GeneTherapyLive.

One example of oncogenicity in animals discussed was the recent clinical hold placed on BioMarin’s phase 1/2 Phearless study (NCT04480567) of gene therapy BMN-307 for the treatment of phenylketonuria (PKU) following tumor development in mice.1

Touching on hepatotoxicity, the committee also discussed the 3 deaths seen in the phase 1/2 ASPIRO trial (NCT03199469) of AT132 in patients with X-linked myotubular myopathy (XLMTM). A fourth death due to liver failure has since occurred and the trial has now been placed on clinical hold for the second time.2 The trial’s first clinical hold was placed following the first 2 deaths in June 2020, and the trial resumed in December 2020. The fourth patient that died was only the first to be dosed since the trial’s resumption. Hepatotoxicity is also fairly common in children treated with Zolgensma, with 2 patients so far experiencing serious liver-related AEs that have resolved.3

"Prudence dictated that the [ASPIRO] trial needs to be suspended until they figure out what's going on. I don't think this should signal a red light for AAV vector, liver directed therapies. It's at least a yellow light. Anybody working in this area should stay updated on these events and see if there's any relevance to the trials they're doing,” Neil Weinreb, MD, FACP, University of Miami UHealth Sylvester Cancer Center Coral Springs and chair, International Collaborative Gaucher Group, told GeneTherapyLive.

AAV gene therapies are not alone in their association with AEs. bluebird bio has also experienced a turbulent timeline with their pipeline of lentiviral vector gene therapies. The FDA previously put a number of the company's studies on hold using the lentiviral vector in February 2021 following the diagnosis of acute myeloid leukemia (AML) in a patient who received the BB305-based gene therapy bb1111 approximately 6 years ago in a phase 1/2 study.4 A patient also developed myelodysplastic syndrome (MDS) in what was categorized as a Suspected Unexpected Serious Adverse Reaction (SUSAR).

The clinical holds were lifted in June 2021 after the company demonstrated that no disruption in gene expression or regulation was found in patients in the β-thalassemia and sickle cell disease trials, and thus the lentiviral vector was not associated with cancer. Two months later, bluebird’s elivaldogene autotemcel (eli-cel) was put on clinical hold following the SUSAR of MDS thought to be mediated by the vector.5 The same therapy was approved in Europe as Skysona in July 2021.

“Dose-related toxicities require understanding the dose. And there have been efforts in the past to try to standardize some reference standards, or make available reference standards that would facilitate comparing clinical findings between studies with human subjects where the dose information is really critical to understanding adverse events,” Byrne told GeneTherapyLive. “Another takeaway from the meeting is the continued and ongoing need that has been in discussion for many years now, for reference standards and reliability and reproducibility in evaluating the product. The critical quality attributes of the gene therapy product are another area where there's been a lot of attention lately.”

1. U.S. FDA placed a clinical hold on BMN 307 Phearless phase 1/2 gene therapy study in adults with PKU based on interim pre-clinical study findings. News release. BioMarin Pharmaceuticals. September 5, 2021.
2. Astellas reports update to September 1 announcement on the ASPIRO clinical trial of AT132 in patients with X-linked myotubular myopathy. News release. Astellas Pharma. September 14, 2021.
3. Chand D, Mohr F, McMillan H, et al. Hepatotoxicity following administration of onasemnogene abeparvovec (AVXS-101) for the treatment of spinal muscular atrophy. J Hepatol. 2021;74(3):560-566. doi:10.1016/j.jhep.2020.11.001
4. bluebird bio announces the lifting of FDA clinical hold for sickle cell disease and β-thalassemia studies. News release. bluebird bio. June 7, 2021.
5. bluebird bio reports second quarter financial results and provides operational update. News release. bluebird bio. August 9, 2021.
6. Cellular, Tissue, and Gene Therapies Advisory Committee September 2-3, 2021 Meeting announcement. US FDA. September 2-3, 2021.
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